Syndromes of altered hormonal homeostasis during human aging are being increasingly understood and invoked to explain such disorders as apathetic hyperthyroidism, benign prostatic hypertrophy and adult-onset diabetes mellitus. Hormonal responsiveness can be quantitated in the diploid human lung derived fibroblast-like cell line WI-38 by measuring stimulation of cellular proliferation. Since this proliferative response has been demonstrated to decline with increasing in vitro age, the age-associated loss of sensitivity to glucocorticoid hormone in WI-38 cells can serve as a model with which to investigate alterations in human hormonal response with aging. The work proposed in this application has four specific aims: 1) Using the new cytosolic glucocorticoid receptor assay for WI-38 cells developed in our laboratory, I will compare characteristics such as molecular weight, requirements for activation and accessibility to the nucleus for receptors from old and young cells. 2) Since target tissues such as fetal skin and fetal lung exhibit opposite proliferative responses to glucocorticoid, I will compare the steps of hormone-receptor interaction in both cell types. 3) I will verify any changes in senescent WI-38 cells using cell lines from older humans as well as lines from patients with syndromes of premature aging. 4) I will examine these initial steps in glucocorticoid hormone action in fibroblasts from patients with an age-associated disease such as diabetes mellitus (adult-onset) in order to examine the relationship between age and disease on hormone action. While conducting these research investigations in geriatric endocrinology, I will be active in a program of patient-care base activities including geriatric medicine in-patient and out-patient visitation, as well as undergraduate and postgraduate teaching in the Department of Medicine at the University of Pennsylvania.